Recurrent breast cancer is typically an incurable disease. As a consequence, the propensity of breast cancers to recur following treatment is the most important determinant of clinical outcome. For many types of human cancer, residual tumor cells - referred to as minimal residual disease - remain following treatment that are not detected by conventional clinical testing. In the case of breast cancer, disseminated tumor cells are present in 20-40% of primary breast cancer patients lacking any clinical or histopathological signs of metastasis. These cells have the ability to survive in a presumed dormant state within tissues for up to 20 years, either as solitary cells or as micrometastases. Ultimately, residual cells re-emerge from this latent state and resume growth, leading to cancer recurrence. As such, minimal residual disease, tumor dormancy, and recurrence constitute fundamental manifestations of tumor progression that are responsible for the vast majority of breast cancer deaths. Despite the unrivaled clinical importance of these aspects of breast cancer progression, however, the mechanisms underlying them are largely unknown. Since dormant residual tumor cells constitute the reservoir from which recurrent cancers invariably arise, the lack of therapeutic approaches specifically targeted against these cells - as well as our lack of understanding about their biology-constitutes major obstacles to the successful treatment of human cancers. As such, the development of targeted therapies designed to block pathways on which residual tumor cells depend for survival and growth would represent an attractive approach to preventing cancer recurrence. To pursue this goal, we have developed and validated a series of doxycycline-inducible transgenic mouse models for MYC, HER2/neu, Wnt1, and Akt-overexpressing breast cancers that display key features of human breast cancer progression, including minimal residual disease, tumor dormancy, and recurrence. In this application, we will use these models to elucidate the molecular pathways that contribute to tumor dormancy and recurrence. The specific aims of this application are to determine the role of the c-Met and Fbw7/Notch pathways, in mammary tumor dormancy and recurrence. Our preliminary data suggest that each of these pathways may promote the survival and recurrence of dormant residual tumor cells. Reducing breast cancer mortality will ultimately require a substantially improved understanding of minimal residual disease, tumor dormancy, and recurrence than currently exists. By probing these critical manifestations of breast cancer progression, the studies proposed in this application will advance the therapeutic goals of maintaining tumor cells in a dormant state or inducing their death by targeting their survival mechanisms. This knowledge could facilitate the development of more effective therapeutic approaches that would dramatically alter the treatment options available to millions of breast cancer survivors. PUBLIC HEALTH RELEVANCE: Residual breast cancer cells that survive therapy have the ability to survive in a dormant state following treatment and linger unrecognized for more than a decade before emerging as recurrent disease. Since recurrent breast cancer is typically an incurable disease, and since recurrent breast cancers typically arise from disseminated tumor cells, understanding the biology of minimal residual disease and elucidating the molecular pathways that contribute to tumor dormancy and recurrence is a critical priority in breast cancer research. This application is focused on that goal.